Diagnosis of Acute Neurologic Emergencies in...

Diagnosis of AcuteNeurologic Emergencies in
Pregnant and Postpartum Women
Andrea G. Edlow, MD, MSca, Brian L. Edlow, MDb,Jonathan A. Edlow, MDc,*

KEYWORDS

� Eclampsia � Posterior reversible encephalopathy syndrome� Reversible cerebrovascular constriction syndrome� Cerebral venous sinus thrombosis � Pregnancy

KEY POINTS

� Pregnant and postpartum patients with headache and seizures are often diagnosed withpreeclampsia or eclampsia because they are the most common conditions; however,other etiologies must be considered.

� Most cases of cerebral venous sinus thrombosis present in the early postpartum period.

� Although stroke and other cerebrovascular diseases are uncommon in pregnant women,the incidence is higher than in age and sex-matched nonpregnant individuals.

� Computed tomography scanning is insensitive to many of the acute neurologic conditionsthat affect pregnant and postpartum women.

INTRODUCTION

Acute neurologic symptoms in pregnant and postpartum women may be owing to anexacerbation of a preexisting neurologic condition (eg, multiple sclerosis or a knownseizure disorder) or to the initial presentation of a non–pregnancy-related problem

Disclosures: None.Contributors: Dr J.A. Edlow wrote the first draft and assumes overall responsibility for thearticle. All of the authors helped to organize the information, write and edit subsequent draftsof the article.Conflicts of Interest: Dr J.A. Edlow receives fees for expert testimony; however, none is felt torepresent a conflict for this article.a Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mother In-fant Research Institute, Tufts Medical Center, 800 Washington Street, Box 394, Boston, MA02111, USA; b Division of Neurocritical Care and Emergency Neurology, Department ofNeurology, Massachusetts General Hospital, 175 Cambridge Street, Suite 300, Boston, MA02114, USA; c Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Har-vard Medical School, One Deaconess Place, West Clinical Center, 2nd Floor, Boston, MA02215, USA* Corresponding author.E-mail address: [email protected]

Emerg Med Clin N Am 34 (2016) 943–965http://dx.doi.org/10.1016/j.emc.2016.06.014 emed.theclinics.com0733-8627/16/ª 2016 Elsevier Inc. All rights reserved.

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Edlow et al944

(eg, a new brain tumor). Alternatively, patients can present with new, acute onsetneurologic conditions that are either unique to or precipitated by pregnancy.In this review, we focus on these latter conditions. The most common diagnostic

tool used in emergency medicine to evaluate many of these symptoms—noncontrasthead computed tomography (CT)—is often nondiagnostic or falsely negative. Misdi-agnosis can result in morbidity or mortality in young, previously healthy individuals.Therefore, if a poor outcome occurs, the medical, social, and medicolegal impact isusually high. For all of these reasons, prompt diagnosis is imperative.The unique pathophysiologic states of pregnancy and the puerperium have been

reviewed.1–4 Increasing concentrations of estrogen stimulate the production of clot-ting factors, increasing the risk of thromboembolism. Increases in plasma and totalblood volumes increase the risk of hypertension. Elevated progesterone levels in preg-nancy increase venous distensibility and, potentially, leakage from small blood ves-sels. The high estrogen levels decrease in the postpartum period. Combined, thesehormonal changes can result in increased permeability of the blood–brain barrierand vasogenic edema.Preeclampsia, the newonset of hypertension and proteinuria or laboratory abnormal-

ities after 20 weeks in a previously normotensive woman, occurs in 2% to 8% ofpregnancies.5 The incidence of preeclampsia has increased by 25% in the UnitedStates over the last 20 years,6 which has been attributed in part to the increase inmaternal obesity and maternal age.7 Diagnostic criteria for preeclampsia were recentlyrevised.8 Whereas previously preeclampsia was defined by systolic blood pressures of140/90 mmHg or greater and proteinuria of 0.3 g or greater of protein in a 24-hour urinespecimen, the new criteria allow for the diagnosis of preeclampsia without proteinuria,permit the use of a spot protein/creatinine ratio or urine dip to diagnose preeclampsia,and rename what was previously called “mild preeclampsia” as “preeclampsia withoutsevere features,” among other changes. Preeclampsia is now defined as blood pres-sures of 140/90 mm Hg or greater on 2 occasions at least 4 hours apart after 20 weeksof gestation in awomanwith a previously normal blood pressure, plus either proteinuria,or in the absence of proteinuria, thrombocytopenia, renal insufficiency, impaired liverfunction, pulmonary edema, or new-onset neurologic symptomssuchas visual changesor headache. In practical terms, this means any woman with persistently increasedblood pressure and a persistent newheadachemeets diagnostic criteria for preeclamp-sia, and the headachewould confer the diagnosis of preeclampsiawith severe features.However, other neurologic conditions requiring significantly different management thanpreeclampsia should be considered in these cases. Of note, the revised criteria statethat severe range blood pressures (those � 160/110 mm Hg) “can be confirmed withina short interval (minutes) to facilitate timely antihypertensive therapy,”8 to stress thatantihypertensive therapy should not be delayed in these women to confirm a diagnosis.Eclampsia is defined as preeclampsia plus a generalized tonic–clonic seizure in the

absence of other conditions that could account for the seizure. Eclamptic seizuresoccur in up to 0.6% of women with preeclampsia without severe features, and in2% to 3% of women with preeclampsia with severe features.9 Of note, eclampsiararely can present atypically, without elevated pressures or proteinuria so it shouldremain on the differential for women with new-onset seizures in pregnancy even ifthe classic criteria of hypertension and proteinuria or laboratory abnormalities arenot satisfied.10–12 Maternal mortality rates for eclamptic women have been reportedto be as high as 14% over the past few decades, with the highest rates in developingcountries.13 Although the most common causes of death in eclamptic women arebrain ischemia and hemorrhage, most eclampsia-related neurologic events are tran-sient, and long-term deficits are rare in properly managed patients.14


Neurological Emergencies in Pregnant and Postpartum Women 945

However, other conditions, which overlap with eclampsia and with each other, canpresent similarly.15,16 These include acute ischemic stroke (AIS), intracerebral hemor-rhage (ICH), subarachnoid hemorrhage (SAH), and cerebral venous sinus thrombosis(CVT). Severe vasoconstriction often develops in women with preeclampsia, espe-cially when the blood pressure is poorly controlled. This vasoconstriction can causebrain infarction and/or hemorrhage. A reversible cerebral vasoconstriction syndrome(RCVS)—also referred to as postpartum angiopathy and Call–Fleming syndrome—candevelop during the puerperium without hypertension or other features of preeclamp-sia. Preeclampsia, eclampsia and RCVS can all be complicated by the posteriorreversible encephalopathy syndrome (PRES). In fact, 8% to 39% of patients withRCVS have PRES as well.17,18 PRES is a clinical (headache, seizures, encephalopathy,and visual disturbances) and imaging (reversible vasogenic edema) syndrome thatmay occur in preeclampsia/eclampsia, RCVS, and other conditions. It is essential torecognize the significant overlap between these various etiologies, which can occurindependently or simultaneously. Whereas eclampsia is specific to pregnancy,PRES, RCVS, and CVT also occur in nonpregnant individuals.This review is intended to help clinicians avoid misdiagnosis in these high-risk pa-

tients. We therefore limit the review to clinical manifestations and diagnosis, becauseonce a given diagnosis is established, specific treatments should naturally follow. Wehave organized the data by presenting symptoms as well as by specific diagnosis.Finally, we have created clinical algorithms based on our interpretation of the existingliterature and our practice.

HEADACHE

Roughly 40% of postpartum women have headaches, often during the first week. Pri-mary headache disorders—tension type and migraine—are the most common causesin both pregnant and postpartum women.19–21 This can paradoxically make correctdiagnosis more difficult unless physicians pay careful attention to “red flags” that sug-gest a secondary cause (Fig. 1B). In 1 series, among 95 patients with severe post-partum headache, one-half had tension type (39%) or migraine (11%), followed bypreeclampsia/eclampsia (24%) and postdural puncture headache (PDPH; 16%).22 Pi-tuitary hemorrhage, mass lesions, and CVT each accounted for another 3%. Thisstudy was skewed toward sicker, hospitalized patients whose headaches were “resis-tant to usual therapy.”In general, migraine improves during pregnancy and returns postpartum as estro-

gen levels decrease.23–25 Pregnant patients with new, worsening headaches,positional headaches, or headaches that have changed in character suggest the pos-sibility of secondary causes. Although new migraines can develop during preg-nancy,26 migraine should be considered a diagnosis of exclusion. Implicit in thediagnosis of migraine and tension-type headache is the presence of multiple episodes(�5 episodes for migraine and�10 for tension-type headache). Therefore, one cannotdefinitively diagnose a first new headache that develops during pregnancy or thepuerperium—or in any other patient for that matter—as a manifestation of a primaryheadache disorder.Preeclamptic patients often have bilateral throbbing headaches accompanied by

blurred vision and scintillating scotomata. Pregnant women with new headachesmust be screened carefully for preeclampsia. Hypertension, epigastric or right upperquadrant abdominal pain, edema, increased deep tendon reflexes, proteinuria, andoccasionally agitation or restlessness may accompany the headache.27–29 Laboratoryfindings that increase the concern for preeclampsia include thrombocytopenia,


Fig. 1. Diagnostic algorithm for pregnant and postpartum patients presenting with acuteneurologic symptoms. (A) Pregnant and post partum women with acute neurologic symp-toms. (B) Pregnant and post partum women with isolated headache. (C) Patients with otherneurologic symptoms or signs (with or without headache and not thought to be pureeclampsia) or eclamptic patterns not responding to treatment. CT, computed tomography;CVT, cerebral venous thrombosis; PRES, posterior reversible encephalopathy syndrome;RCVS, reversible cerebral vasoconstriction syndrome; SAH, subarachnoid hemorrhage.

Edlow et al946

hemoconcentration, transaminitis, elevated creatinine, and elevated uric acid. Unfor-tunately, despite considerable research and progress, there is no current routinelyavailable biomarker to definitively diagnose preeclampsia.30,31

Patients with abrupt onset of a severe, unusual headache (“thunderclap headache”)require urgent investigation.32 Large studies evaluating the possible increasedincidence of SAH in pregnant and postpartum patients report mixed results, possiblyowing to varying methods of case acquisition, as well as the fact that some instancesof SAH in these patients are nonaneurysmal.33–36 Hormonal changes affectingcerebral blood vessels and surges in blood pressure from pushing during labor are



2 potential mechanisms for an increased incidence of aneurysmal SAH.34 All patientspresenting with a thunderclap headache require a thorough evaluation to excludeSAH, usually a head CT scan followed by lumbar puncture if the CT scan isnondiagnostic.However, if the workup for SAH is negative, disorders such as PRES, CVT, RCVS,

and cervicocranial arterial dissections must be considered in pregnant and post-partum patients who present with thunderclap headache (Fig. 1). Because CT andlumbar puncture may both be negative in these latter conditions, physicians shouldstrongly consider following up a nondiagnostic CT and lumbar puncture with MRI se-quences including diffusion-weighted images as well as vascular studies of the ar-teries (MR angiogram) and veins (MR venogram). If arterial dissection is suspected,acquisition of T1 fat-saturated images should be considered to increase the sensitivityfor detecting a thrombus within a dissection flap.37

In patients who have had a spinal or epidural anesthetic, PDPH is an importantconsideration, and has been estimated to occur in 0.5% to 1.5% of these pa-tients.38–40 Caused by low intracranial pressure owing to a cerebrospinal fluid leak,headaches, often nuchal and occipital, typically begin 1 to 7 days postpartum, rapidlyworsen upon standing, and resolve upon lying flat over 10 to 15 minutes.20,39 Tinnitus,diplopia, and hypacusia may occur.20 Symptoms usually resolve within 48 hours of ablood patch. Patients who have not had a spinal or epidural anesthetic may alsodevelop postpartum low-pressure headaches, presumably owing to dural tears fromlabor-related pushing.Rare complications of PDPH include subdural hematoma, PRES, and CVT.41–43 Low

intracranial pressure can cause subdural hematoma from the tearing of bridging veinsthat become taut as the brain sags.39 Clues to this complication include loss of thepostural component of headache (owing to the offsetting effects of low intracranialpressure from the dural puncture and elevated pressure from the subdural hematoma)and lack of response to a blood patch.Most serious causes of headache are more common postpartum than during preg-

nancy. Therefore, if migraine or PDPH is not likely based on the history and neurologicexamination, physicians must consider these other etiologies.

ACUTE NEUROLOGIC SYMPTOMS AND DEFICITS

Pregnant or postpartum patients who present with acute motor, sensory, or visualfindings (with or without headache) may have more serious causes and require urgent,thorough evaluation (see Fig. 1). Pregnant patients with acute neurologic deficits mostoften have migraine with aura, even in the absence of headache (ie, acephalgicmigraine). Two studies using different methods both found that of pregnant patientsreferred for transient motor, sensory or visual symptoms, the vast majority could beultimately attributed to migraine with aura.44,45

Historical clues for a migrainous etiology include gradual onset of the neurologicsymptoms and positive phenomenon (such as brightness or shimmering) as opposedto negative ones (blackness or loss of vision).23 The gradual onset and slow progres-sion over 15 to 30 minutes differentiates migrainous symptoms from those attributableto cerebral ischemia, which are typically maximal at onset, and seizure, which spreadmore rapidly (ie, over seconds). Another clue that may help to differentiate migrainefrom vascular thromboembolic disease is the pathophysiologic process of corticalspreading depression that is believed to cause migrainous neurologic deficits oftencrosses vascular territories. Migrainous positive phenomena (brightness or sparklingin vision, tingling or prickling feelings in the limbs or body) often leave in their wake


Edlow et al948

transient loss of function (scotoma or numbness). Symptoms affecting 1 modality (eg,vision) may clear and then involve another modality (eg, sensation).Because visual symptoms are common with preeclampsia, one must be cautious

not to make that diagnosis without considering other possibilities such as PRES, pi-tuitary apoplexy or tumor growth, and strokes affecting the visual pathways. Becausepituitary adenomas (micro or macro) may grow during pregnancy, any woman with aknown pituitary tumor and new onset of headache with or without diplopia and abitemporal field cut should undergo emergent pituitary imaging.46 Another consider-ation is orbital hemorrhage, which presents as acute diplopia, proptosis, and eyepain, and can occur during the first trimester (from hyperemesis) or during labor(from pushing).46,47

Overall, stroke in pregnant and postpartum women is rare; however, the risk isincreased compared with nonpregnant age-matched controls, especially in late preg-nancy and the early puerperium.33,48 Recent evidence suggests that the rate of preg-nancy- and postpartum-associated strokes is increasing.49,50 This epidemiologictrend is true for patients with and without pregnancy-related hypertensive disorders.50

The event rates per 100,000 deliveries range from 4 to 11 (AIS), 3.7 to 9 (ICH), 2.4 to 7(SAH), and 0.7 to 24 (CVT).33,48,49,51–54 These epidemiologic studies varied in theirmethodology (Table 1). The wide range for CVT likely reflects variability in the case-finding definitions and radiologic modalities. Moreover, the extremely low strokerate in the most recent study is likely owing to the fact that postpartum patients (theperiod of highest risk) were not included.55

Preeclampsia/eclampsia plays an etiologic role in 25% to 50% of pregnant andpostpartum patients with strokes: highest with ICH, lower in AIS, and lowest withCVT.33,48,51,54,56 Other stroke risk factors in these women include older age, AfricanAmerican race, congenital and valvular heart disease, hypertension, caesarian deliv-ery, migraine, thrombophilia, systemic lupus erythematosus, sickle cell disease, andthrombocytopenia.49,50,52,53 In an analysis of 347 cases of fatal pregnancy-relatedstrokes over a 30-year period in the United Kingdom, these patients accounted for1 in 7 maternal deaths.57 Themes that emerged from analysis of these 347 fatal caseswere failure to recognize and treat hypertension, delays in imaging owing to concernsabout radiation exposure, delays in senior physician involvement, and diagnosticanchoring of “hysteria” or drug-seeking behavior.57

Thrombocytopenia also suggests the HELLP syndrome (hemolysis, elevated liverenzymes, low platelets) and thrombotic thrombocytopenic purpura (TTP), whose inci-dence is elevated in pregnancy and which can present with strokelike symptoms.58

These 2 conditions have very different clinical courses and management, somaternal–fetal medicine and hematology experts should be involved immediately inthe evaluation, particularly if TTP is on the differential. One study of 1166 deliveriesfound 12 cases of HELLP syndrome of which 8 had neurologic complications—namely, seizures (4 patients), focal deficits (2 patients), and encephalopathy (2 pa-tients).59 On imaging, 6 patients had PRES (3 with associated hemorrhages) and 2had isolated ICH.59

Another unusual cause of stroke in pregnant and postpartum women is cervicocra-nial arterial dissection. There may be an increasing frequency in pregnant and post-partum women, although comprehensive epidemiologic data are lacking.60 Patientswith cervicocranial arterial dissections often present with isolated headache and/orneck pain without neurologic deficit,61 but they can also present with focal deficitsowing to embolic strokes.62,63 There may be a predisposition for multiple vessel dis-sections.64 In the largest series of 8 postpartum cases, the only differences betweenpostpartum cases and those occurring in nonpregnant/postpartum women were that


Table 1Incidence of stroke in pregnant and postpartum women, per 100,000 deliveries

Study, YearPublished AIS ICH SAH CVT Eclampsia

Comments (Methods,Total Deliveries, Yearsof Analysis)

Sharshar et al,54

19954.3 4.6 — — 47% of AIS

44% of ICHPopulation-basedregional Frenchstudy

348,295 deliveries1989–1991

Kittner et al,48

199611 9 Excluded — 25% of AIS

15% of ICHPopulation-basedregional US study

141,243 deliveries1988–1991

Jaigobin & Silver,51

200011.1 3.7 4.3 6.9 23% of AIS

38% of CVT17% of ICH0% of SAH

Referral single-centerCanadian study

50,700 deliveries1980–1997

Lanska & Kryscio,53

2000b13a a a 12.1 Not reported US national inpatient

database1,408,015 deliveries1993–1994

Salonen Ros et al,33

20014.0 3.8 2.4 — Not reported Population-based

national Swedishstudy

1,003,489 deliveries1987–1995

James et al,52 2005b 9.2 8.6 — 0.7 15.7c US national inpatientdatabase

8,322,799 deliveries2000–2001

Kuklina et al,49

2011b11 7 7 24 Not reported US national inpatient

database8,786,475 deliveries2006–2007

Scott et al,55 2012Note: included

prenatal eventsonly; see text

0.9d 0.4e — — 11% of AIS33% of ICH

(preeclampsiaand eclampsia)

United Kingdomnational population-based cohort andnested case-controlstudy

1,958,203 deliveries2007–2010

Abbreviations: AIS, acute ischemic stroke; CVT, cerebral venous thrombosis; ICH, intracerebral hem-orrhage; SAH, subarachnoid hemorrhage.

a The 13 includes AIS, ICH and SAH in this study.b Intrinsic to the studies using the US national database is a sampling of approximately 20% of

patients. Therefore, the reported number of deliveries is an extrapolated number.c The authors do not directly state which strokes are eclampsia-related but do include an Inter-

national Classification of Disease, 9th edition (ICD-9) code for “pregnancy-related cerebrovascularevents” separate from the ICD-9 codes for AIS, ICH, or CVT.

d Includes CVT.e Includes SAH.



Edlow et al950

simultaneous PRES, RCVS, and SAH were more often seen in the postpartum cases,again emphasizing the theme of overlapping clinical syndromes in these patients.61

The vast majority of these dissections occur postpartum.65

Data from a small case series suggests that women with a prior cervical arterydissection without an underlying connective tissue disorder may not be at significantlyincreased risk for subsequent pregnancy-related dissections.66 Still, this seriesincluded only 11 women with completed pregnancies after the index event, only 1of 11 had the initial event in the peripartum period, and 7 subsequent pregnancieswere delivered by cesarean, suggesting possible confounding by indication, so thedata must be interpreted with caution.In patients with ICH and SAH, underlying structural lesions such as vascular malfor-

mations and aneurysms are relatively common.48,51,54,56 SAH that occurs around thecircle of Willis suggests an aneurysm, whereas convexal SAH suggests RCVS or CVT(with or without an associated cortical vein thrombosis). Brain infarction and hemor-rhage can result from many of the vasculopathies, including RCVS and preeclampsia.Finally, TTP, pituitary apoplexy, choriocarcinoma, amniotic fluid embolism, air embo-lism, and cardioembolism from postpartum cardiomyopathy are rare causes of strokein this population.16,67 Sufficient diagnostic testing including vascular imaging must beperformed in these patients to identify specific treatable causes.

SEIZURES

Pregnant or postpartum women with seizures can be grouped into 3 categories. Themost common are patients with an established seizure disorder before pregnancy.68

Of note, again demonstrating the frequency of overlapping clinical syndromes, womenwith epilepsy before pregnancy have an increased likelihood of developing pre-eclampsia, and of progressing to eclampsia.69 The second group includes patientswith a new non–pregnancy-related seizure disorder, such as a new seizure from an un-diagnosed brain tumor or hypoglycemia. These pregnant and postpartum patientsrequire the same systematic approach to a new seizure as in all seizure patients,but are not the focus of this review.The third group has new seizures that are pregnancy related. Important causes

include eclampsia, ICH, CVT, RCVS, PRES, and TTP. Seizures are very common inPRES and usually occur at presentation in the absence of prodromal symptoms,whereas in CVT seizures usually occur later and nearly always after headache.16

Head CT scans can be normal in each of these conditions. Seizures are much lesscommon in RCVS.70

Data are lacking to direct the initial workup in these patients. However, because ofthis wide differential diagnosis and lack of sensitivity of CT scanning, we believe thatpregnant and postpartum patients with new-onset seizures, even those who havereturned to baseline and are neurologically intact, should undergo sufficient workup,which usually includes MRI, to establish the cause of the seizure. Postpartum women,even those who are breastfeeding, should undergo the same neuroimaging study thatwould be done in any other patient for the same indication. For antepartum patientswhose optimal neuroimaging would normally involve gadolinium, maternal–fetal med-icine should be consulted to discuss the risks versus benefits of gadolinium adminis-tration in this setting.

INDIVIDUAL CONDITIONS

The clinical presentations of the specific conditions have considerable overlap andcan coexist. However, the details (eg, characteristics of headache, evolution of



symptoms over time, and frequency of some symptoms such as seizures or visualproblems) can often help to distinguish among them (Table 2).

CEREBRAL VENOUS SINUS THROMBOSIS

A rare cause of stroke overall, CVT is an important consideration in pregnant and post-partum women.71–74 There is a spike in the incidence during the first trimester, prob-ably owing to women with an underlying thrombophilia who become pregnant56;however, more than 75% of cases occur postpartum.75 Although the greatest riskfor postpartum thromboembolism is in the first 6 weeks, the risk probably extendsout to 12 weeks.76 Risk factors include caesarian section, dehydration, traumatic de-livery, anemia, increased homocysteine levels, and low cerebrospinal fluid pressureowing to dural puncture.42,53 CVT is posited to be more common in developing coun-tries owing to the increased frequency of poor nutrition, infections, and dehydra-tion.77,78 CVT owing to pregnancy or oral contraceptive use tend to have betterlong-term outcomes than men or women with CVT unrelated to pregnancy.75

Most patients with CVT present with a progressive, diffuse, constant headache,although in 10% it is a thunderclap headache.79,80 However, 10% of patients withCVT may have no headache at all.81 Other findings include dizziness, nausea, sei-zures, papilledema, lateralizing signs, lethargy, and coma. The specific presentationdepends on the extent and location of the involved dural sinuses and draining veins,collateral circulation, effects on intracranial pressure, and presence of associatedhemorrhage.82 Symptoms vary and may fluctuate over time.42,71,78 Neurologic deficitsdo not follow arterial distributions.Although D-dimer is usually increased in patients with CVT, most do not recommend

its use in pregnant and postpartum women.83,84 These patients are often D-dimer pos-itive, especially late in pregnancy and in the early puerperium.85 Pending furtherstudies, we do not recommend using a negative D-dimer in pregnant or postpartumwomen to exclude CVT. Noncontrast CT scans are often negative, but may show ahyperdense venous clot or signs of infarction in 30% of cases84 (Fig. 2). Ischemic in-farcts often undergo hemorrhagic transformation owing to venous hypertension. CTvenography often shows the clot, but MRI with MR venogram, gradient recalledecho, and contrast-enhanced magnetization-prepared rapid gradient echo se-quences is typically diagnostic and considered the imaging study of choice.84

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME

RCVS is characterized by abrupt onset of usually multiple thunderclap headachesand multifocal, reversible cerebral vasoconstriction, typically occurring during thefirst week after delivery.86 Recurring daily thunderclap headaches over several weeksthat follow a single thunderclap headache may be pathognomonic.86–88 When relatedto pregnancy, two-thirds of patients with RCVS develop symptoms within 1 weekof delivery and after a normal pregnancy.18 RVCS is also associated with use ofimmunosuppressive drugs, vasoactive medications (eg, serotonin reuptake inhibitorsand phenylpropanolamine), recreational drugs (eg, cocaine and marijuana), bloodproducts, catecholamine-secreting tumors, craniocervical arterial dissections, andvarious other miscellaneous conditions.18 In a review of a large series of RCVSand arterial dissections designed to identify patients with both conditions simul-taneously, the postpartum state emerged as an association of this overlap.89 Vomit-ing, confusion, photophobia, and blurred vision often accompany the headaches.When seizures or focal neurologic deficits develop, they nearly always follow theheadache.


Table 2Distinguishing clinical and imaging features of selected conditions

PRES RCVS CVT Eclampsia

Mode ofonset

Rapid (over hours),usually postpartum

Abrupt, usually postpartum Third trimester or postpartum.Symptoms often progress over days.

Antepartum, intrapartum orpostpartum (10%–50%)

Prominentfindings

Early prominent seizuresUsually seizures plus at least other

symptoms (stupor, visual loss,visual hallucinations)

HA dull and throbbing, notthunderclap

Thunderclap HA, multiple episodesSeizures occur but much less so than

in PRESTransient focal deficits (may become

permanent in cases with ICH orinfarction)

HA nearly universal at onset,generally progressive and diffuse,thunderclap in small minority

Seizures occur in w40%Focal signs may develop later

Seizure, frequent visualsymptoms and abdominalpain, hyperreflexia,hypertension, proteinuria

Evolutionover time

Symptoms resolve over days to aweek if blood pressure controlled

Dynamic process over time; as ageneral rule, HAs are commonduring first week, ICH during thesecond week and ischemiccomplications during the thirdweek

Evolves over several days;nonarterial territorial infarcts andhemorrhages may develop

Can evolve (frompreeclampsia) graduallyor abruptly

CSF findings Usually normal, may have slightlyelevated protein

Often normal (unless complicatedby SAH) but 50% will have slightpleocytosis and protein elevations

Opening pressure elevated w80%of cases

w35%-50% will have slightelevations of protein or cells

Usually normal unlesscomplicated byhemorrhage

Imagingaspects

CT positive in w50% of casesMR prominent T2-weighted and

FLAIR abnormalities nearly alwaysin the parietooccipital lobes butcan involve other parts of thebrain

ICH in w15% of patients

CT usually normal (if no SAH)MR – 20% with localized convexal

SAHCTA, MRA usually shows typical

“string of beads” constriction ofcerebral arteries

DSA is more sensitiveMay have associated cervical arterial

dissectionInitial arteriogram may be negative

CT often negativeMR may show nonarterial territorial

infarctsHemorrhage commonMRV shows intraluminal clot flow

voidsAlthough MRV is preferred, CTV is

also sensitive

Same as for PRESSome patients may have

coincident AIS or ICH

Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; CTA, CT angiogram; CTV, CT venogram; CVT, cerebral venous thrombosis; DSA, digital subtrac-tion angiogram; FLAIR, fluid-attenuated inversion recovery; HA, headache; ICH, intracerebral hemorrhage; MRA, MR angiogram; MRI, magnetic resonance imag-ing; MRV, MR venogram; PRES, posterior reversible encephalopathy syndrome; RCVS, reversible cerebral vasoconstriction syndrome.

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Symptoms usually subside over several weeks.70,86,87,90 Although most patientshave good outcomes, there is considerable variability in disease progression andfatal outcomes have been reported in postpartum patients with RCVS.17,91 Thereversibility refers to the angiographic vasospasm, not to the clinical outcomes.Complications include nonaneurysmal convexal SAH, ICH, and AIS.70,86–88,90,92,93

Convexal SAH is more common than parenchymal ICH.93 Hemorrhagic complica-tions usually precede ischemic ones.86 In patients without infarction, the disease re-solves over time. Up to 10% of patients with RCVS may also have cervicocranialarterial dissections.89 Unless there is a complicating hemorrhage, the cerebrospinalfluid is usually normal, but may show small numbers of lymphocytes and mildlyelevated protein.70,86

Absent a hemorrhage, the CT scan is usually normal. With regard to vasculartesting, it is important to recognize that RCVS is a dynamic process. TranscranialDoppler ultrasonography and various forms of angiography are useful tools; however,they may be normal early in the course of the disease. Angiography and transcranialDoppler ultrasonography may be discordant.18 Angiography reveals multifocalsegmental arterial constriction and can also detect arterial dissections.92 By definition,focal areas of arterial constriction on catheter angiography are always present. How-ever, it is important to recognize 2 limitations of noninvasive angiography (MR angio-gram or CTA): (1) these modalities are only positive in approximately 80% of patients,showing the diagnostic pattern of alternating dilatation and constriction, simulating a“string of beads” (see Fig. 2)86,94; and (2) CTA andMR angiogrammay be normal in thefirst 5 to 6 days of RCVS.18,94 Transcranial Doppler ultrasonography can be used tofollow resolution of the vasoconstriction.95

POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME

PRES is a syndrome characterized by headache, seizures, encephalopathy, and visualdisturbances in the setting of reversible vasogenic edema on CT scan or MRI.96,97

PRES occurs in patients with acute hypertension, preeclampsia or eclampsia, renaldisease, sepsis, exposure to immunosuppressant drugs, and numerous other condi-tions and drug exposures.98–100 In a single-center series, 46 of 47 patients witheclampsia (98%) had PRES, suggesting that in the setting of eclampsia, PRES is anintegral part of the pathophysiology.101 Early diagnosis and management mayimprove outcomes.102

Symptoms develop without prodrome and progress rapidly over 12 to 48 hours. Sei-zures, which occur in approximately 75% to 90% of patients, may be focal initially,then become generalized tonic–clonic. Severe symptoms can occur even in theabsence of severe hypertension.97,103 Headache occurs in roughly 50% of patients.97

The headache is generally dull, bilateral, and not thunderclap in nature. Some degreeof encephalopathy, ranging frommild confusion to stupor and coma, is present in 50%to 80% of patients.97

Because the vasogenic edema typically involves the occipital lobes, approximately40% of patients have visual symptoms, including visual hallucinations, blurred vision,scotomata, and diplopia.97,104 Transient cortical blindness occurs in 1% to 15% of pa-tients. The retina and pupils are normal. Consider electroencephalographic monitoringto detect electrical seizure activity in encephalopathic patients without overt seizureactivity (ie, nonconvulsive status epilepticus).97 CT scans will show edema in about50% to 60% of patients.105,106 However, MRI should be performed when PRES is sus-pected because of its increased sensitivity for detecting vasogenic edema, microhe-morrhages, and other PRES-related intracranial pathology.


Fig. 2. Selected patient images. (A) Noncontrast CT scan of a 21-year-old woman who pre-sented with 7 days of increasing left-sided headache. A subtle increased density (black ar-rows) that is consistent with clot in the left transverse sinus can be seen. (B) The MR

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MRI reveals focal edema, nearly always in the parietooccipital lobes (see Fig. 2).Although the mechanism of this posterior predominance has not been fully elucidated,it is hypothesized that the posterior cerebrovascular circulation has less autoregula-tory capacity than does the anterior circulation in the setting of increased cerebralperfusion pressure. Nevertheless, regions of the brain supplied by the anterior cere-brovascular circulation are often involved concomitantly.107,108 The visual symptomsoften resolve completely in hours to days; resolution of the edema on imaging lagsbehind.109,110 In eclamptic patients, PRES is not the only potential explanation for sei-zures. Although most pregnant or postpartum women with PRES have eclampsia,other contributing factors (such as medication use or RCVS) are also possible.Studies comparing clinical and radiological features of PRES in nonpregnant versus

pregnant patients have reported mixed results. One small study (21 patients) found nodifferences.111 In a larger study (96 patients), eclamptic or preeclamptic patients withPRES more commonly presented with headache, and were less likely to be confusedand more likely to have visual symptoms.112 A third study (38 patients) also found lessalteration in mental status in pregnant versus nonpregnant patients with PRES, as wellas overall lower systolic blood pressures.113 On imaging, pregnant patients had lessedema, fewer hemorrhages, and more complete resolution.112 In another study of70 patients with “severe” PRES admitted to an intensive care unit, pregnancy or post-partum states (23% of the patients) were associated with better 90-day outcomesthan other patients with PRES.114 Given the small numerators (pregnant and post-partum patients) and denominators (total PRES patients) of these studies, it is difficultto draw firm conclusions about the impact of pregnancy on presentation or prognosis.

NEUROLOGIC COMPLICATIONS OF ECLAMPSIA

Seizures are the hallmark of eclampsia. Eclamptic seizures are usually tonic–clonicand last approximately 1 minute. Symptoms that can precede seizures include persis-tent frontal or occipital headache, blurred vision, photophobia, right upper quadrant orepigastric pain and altered mental status. In up to one-third of cases, there is no pro-teinuria or blood pressure is less than 140/90 mm Hg before the seizure.10

Although the exact mechanism of eclamptic seizures is unknown, several hypothe-ses have been proposed.115 Overactivity of cerebrovascular autoregulation inresponse to hypertension can lead to cerebral arterial vasospasm and ischemia,resulting in cytotoxic edema. Alternatively, loss of autoregulation in response to hyper-tension leads to endothelial dysfunction, capillary leak, and vasogenic edema.9,115,116

This vasculopathy can also result in PRES or regions of infarction and hemorrhage.117

=venogram from the same patient shows a clot in the left transverse sinus (short wide arrow)and in the sigmoid sinus (long thin arrow). (C) Selected images from a digital subtractionangiogram of a patient with reversible cerebral vasoconstriction syndrome who presentedwith a thunderclap headache. The image on the left shows the diffuse nature of the vaso-constriction. The image on the right shows the classic “string of beads” appearance (blackarrows show the focal areas of vasoconstriction). Similar findings are seen in most patientswith noninvasive (compute tomography or MR) angiography. (D) Two images from theT2-weighted fluid-attenuated inversion recovery (FLAIR) sequence on an MRI showincreased signal in the bilateral parietooccipital regions (white arrows), slightly more onthe right, in a 29-year-old patient with posterior reversible encephalopathy syndrome.Diffusion-weighted imaging on this same patient was normal. Note that the bilateral FLAIRhyperintensities, indicating vasogenic edema, spare the medial occipital lobe and calcarinecortex, which distinguishes this finding from posterior cerebral artery ischemic lesions.


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Although focal vasogenic edema is characteristic of eclampsia, up to one-quarter ofpatients have areas of persistent cytotoxic edema consistent with infarction or focalhemorrhage.116 In 1 study, one-third of patients with “eclamptic encephalopathy”had cytotoxic edema.118 Thus, components of PRES, areas of ischemia or hemor-rhage, and even RCVS may also contribute to eclamptic seizures.Approximately 90% of eclampsia occurs at or after 28 weeks of gestation.13 Just

more than one-third of eclamptic seizures occur at term, developing intrapartum orwithin 48 hours of delivery.13 Although a large population-based study in Californiasuggests that the incidence of eclampsia in the United States is decreasing,119 recentdata suggest an increase in “late” postpartum eclampsia (>48 hours after delivery).13

In 1 large study of postpartum diagnoses of preeclampsia/eclampsia, two-thirds ofpatients had been discharged and were readmitted because of late postpartum pre-eclamptic symptoms, most commonly headache.120 Of these 151 patients withdelayed postpartum preeclampsia, approximately 16% of those readmissions werecomplicated by eclampsia. The proportion of preeclampsia/eclampsia diagnosedpostpartum ranges from 11% to 55% and may be increasing owing to improved ante-partum recognition.121–124 Postpartum patients sometimes ignore early symptoms,such as headache or abdominal pain, and only seek medical care later, after aseizure.121,125

Patients with postpartum eclampsia, especially those with late postpartumeclampsia, have an higher incidence of CVT, ICH, and AIS.13,126 If an experiencedclinician thinks that a woman has typical eclampsia, brain imaging is not necessarilyindicated.13 However, in postpartum eclamptic patients, those with focal neurologicdeficits, persistent visual disturbances, and symptoms refractory to magnesium andantihypertensive therapy or in patients for whom there is any diagnostic uncertainty,a thorough diagnostic workup, preferably including MRI, is recommended. Imagingmay also reveal areas of vasoconstriction consistent with RCVS. Rarely, pregnant pa-tients, especially those with RCVS, develop craniocervical arterial dissections.61–63,127

Thus, the spectrum of neurologic imaging findings in preeclamptic/eclamptic patientsincludes infarction, hemorrhage, vasoconstriction, dissection, and both vasogenicand cytotoxic edema.

RARE CONDITIONS CAUSING ACUTE NEUROLOGIC SYMPTOMS IN PREGNANT ANDPOSTPARTUM WOMEN

Amniotic fluid embolism and metastatic choriocarcinoma are 2 rare pregnancy-specific conditions that can present with acute neurologic symptoms. In a single-center series, only 10 cases of amniotic fluid embolism were found over 30 years.128

One-half of these cases presented with postpartum hemorrhage and one-half pre-sented with cardiovascular collapse.128 The latter presentation is associated withagitation, confusion, seizures, and encephalopathy with cardiopulmonary collapseoccurring during or immediately after labor.129,130 Choriocarcinoma, a rare malignancyof trophoblastic tissue, metastasizes to the brain in 20% of patients.131,132 Becausethe tumor can cause hemorrhage, mass effect, and invasion of cerebral vessels, itsclinical and imaging manifestations are variable.132,133

Air embolism occurs when air that enters the myometrium during delivery isabsorbed into the venous circulation and right ventricle, reducing cardiac output.Nearly any focal or generalized neurologic symptom can occur owing right-to-leftintracardiac shunting of air via a patent foramen ovale.134 Alternatively, air may enterthe left-sided arterial circulation via transpulmonary shunting of blood. Air emboli maythen occlude the cerebral microvasculature, resulting in cerebral ischemia and/or



seizures during or just after delivery.134 The presence of air in the retinal veins and a“mill wheel” cardiac murmur suggest the diagnosis.Another important consideration is Wernicke’s encephalopathy, which, although

classically associated with alcohol use and malnutrition, can also complicate hyper-emesis gravidarum. Among 625 nonalcoholic patients with Wernicke’s encephalopa-thy, 76 (12%) were in women with hyperemesis.135 Abnormal eye movements arenearly always present; however, the classic triad of confusion, ocular findings(diplopia and nystagmus), and gait abnormalities occurs in a minority of patients.136

Some patients have an otherwise unexplained metabolic acidosis.137 Neitherbiochemical confirmation nor MRI is necessary, the simplest test being the responseto intravenous thiamine.135–137 It is essential to administer intravenous thiamine beforeadministration of glucose-containing intravenous fluids in pregnant women with se-vere hyperemesis to avoid provoking neurologic injury in the setting of thiaminedeficiency.Pregnant women are at particular risk for TTP, which most commonly presents late

in the second or early third trimesters.58,138 The classic pentad includes thrombocyto-penia, microangiopathic hemolytic anemia, fever, and neurologic and renal dysfunc-tion.139 Neurologic manifestations, occurring in more than one-half of patients,include fluctuating headache, seizures, and generalized and focal neurologic deficits.Coexistent PRES is common.140 Because the treatments are so different, distinctionbetween TTP (plasma exchange) and HELLP (magnesium and delivery of the fetus)is important.58,138,140 Given that there is no single distinguishing feature, hematologicand maternal–fetal medicine consultation is strongly recommended.Pituitary apoplexy, acute infarction, or hemorrhage of the gland, usually in the setting

of a (previously undiagnosed) adenoma, presents with headache, visual loss, varyingdegrees of ophthalmoplegia, and decreased level of consciousness. Although the pi-tuitary gland enlarges during pregnancy, pregnancy is a rare precipitant for pituitaryapoplexy.141,142 Pituitary apoplexy must be distinguished from Sheehan syndrome(hypopituitarism presenting indolently, weeks tomonths after severe postpartum hem-orrhage)143 and lymphocytic hypophysitis (presents in pregnant patients with head-ache and visual symptoms but typically with a slower onset).144

NEUROIMAGING AND MULTIDISCIPLINARY COORDINATION OF CARE

Most of these patients require brain imaging to make a specific diagnosis. Severalbasic principles should be kept in mind. First, the emergency physician should discussthe differential diagnosis with the other consultants (including the radiologist) beforeimaging. The goals of imaging are to minimize ionizing radiation and intravenouscontrast exposure, and ensure that, when MRI is being performed, the correct se-quences are obtained the first time to optimize the diagnostic yield. Second, the fetalradiation exposure from a noncontrast brain CT scan is negligible.145 Although CTscanning is safe to perform in this population, clinicians must realize its diagnostic lim-itations for many of the target conditions. Third, becausemany of these conditions thatcause acute neurologic symptoms and signs in pregnant and postpartum patientsrequire MRI to establish the diagnosis, the clinician’s threshold for proceeding directlyto MRI must be accordingly low. MRI in pregnant patients is generally thought to besafe, although conclusive data are lacking.145–147 Until recently, there were no re-ported teratogenic or other adverse fetal effects of iodinated contrast.148–150 InSeptember 2015, a report was published describing thyroid dysfunction in 5 of 212Japanese neonates born to women who underwent hysterosalpingogram with ethio-dized oil (an iodinated contrast medium) before becoming pregnant.151 Given that this


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is a single report in the medical literature, as well as the lack of clarity as to how pre-pregnancy hysterosalpingogram exposure to ethiodized oil relates to pregnant womenreceiving intravenous iodinated contrast, this report must be interpreted verycautiously. Because repeated supraclinical doses of gadolinium have been associatedwith fetal demise and malformations in animal studies, gadolinium is best avoided un-less the physician believes that the information to be gained by its use exceeds its po-tential risk.145,152

Authorities recommend obtaining informed consent before these procedures anduse of intravenous contrast agents.145,146,152 However, in an emergent situation,necessary imaging should not be delayed if the patient is unable to give consentand a surrogate decision maker is not readily available. Last, because only minuteamounts of both iodinated contrast and gadolinium are secreted in breast milk andbecause similarly minutes quantities are absorbed across an infant’s gut, both typesof contrast are considered to be safe in postpartum with respect to breastfeeding.145,152

No data address the effects on outcomes of location of care of pregnant and post-partum patients with acute neurologic emergencies. Our opinion is that because thesesituations are uncommon and inherently multidisciplinary, these patients are ideallycared for in hospitals that have neurologic, neurosurgical, advanced radiological, ob-stetric, and critical care expertise. Even in such centers, close coordination of careacross various disciplines is key.

SUMMARY

Pregnant and postpartum patients who present with acute neurologic symptomsrequire a thorough diagnostic evaluation that targets a broad range of pathologicconditions that are either unique to or occur more frequently in this population.Once an accurate diagnosis is made, specific therapy can follow. Because of themultidisciplinary nature and relative infrequency of most of these conditions, werecommend that emergency physicians work closely with various consultants to co-ordinate care in these patients. Early transfer of these patients to a center capableof delivering the full range of diagnostic testing and potential care should beconsidered.

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